High to low dose

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987 Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of... 

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

Burch (1983) suggests that repair mechanisms cause a non neglectible complication for extrapolation from high to low doses and presents a modification of the linear-quadratic formula given above. Katz and Hofmann (1982) carried out an analysis of particle tracks with the result that they find no basis for a linear or linear-quadratic extrapolation to low doses. Van Bekkum and Bentvelzen (1982) present a hypothesis of the gene transfer-... 

These three commonly encountered problems in dealing with the dose-response step of the risk assessment process (and there are others as well) are respectively referred to as the problems of (1) high-to-low dose extrapolation (2) extrapolation across exposure durations ... 

Data on the toxicokinetics of a substance can be very useful in the interpretation of toxicological findings, and may replace the use of some default extrapolation factors used in route-to-route (Section 5.5) or interspecies extrapolations (Section 5.3). In addition, interindividual differences in sensitivity to toxicants may be identified on the basis of toxicokinetic data, thereby making it possible to make the risk assessment more comprehensive by including sensitive subpopulations (Section 5.4). In conjunction with information on the relationship between concentration-dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

In conjunction with information on the relationship between concentration/dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

Method of high-to low-dose extrapolatan Lifetime cases per million exposed Cases per 50 million per year... 

The extrapolation from high to low doses will depend on the type of primary toxic effect. If this is a carcinogenic effect, then a threshold normally cannot be assumed, and a mathematical model is used to estimate the risk at low doses (see above). If the primary toxic effect is noncarcinogenic, then it will normally be assumed that a threshold exists. 

Since responses at the low dose levels of concern in routine exposures of the public cannot be measured directly in animal or human epidemiologic studies, a number of approaches have been developed to extrapolate from high to low doses. Different extrapolation approaches may fit the observed data reasonably well but lead to large differences in the projected responses at low doses (see Section 3.2.1.5.2). 

For the most frequently used low-dose models, the multi-stage and one-hit, there is an inherent mathematical uncertainty in the extrapolation from high to low doses that arises from the limited number of data points and the limited number of animals tested at each dose (Crump et al., 1976). The statistical term confidence limits is used to describe the degree of confidence that the estimated response from a particular dose is not likely to differ by more than a specified amount from the response that would be predicted by the model if much more data were available. EPA and other agencies generally use the 95 percent upper confidence limit (UCL) of the dose-response data to estimate stochastic responses at low doses. 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

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